Mayo Collaborative Services v. Prometheus Laboratories -- What Should We Do? (or Can These Claims Be Saved?)

Perhaps unintentionally, the Supreme Court issued a challenge to America's patent attorneys in its Prometheus decision, warning against "interpreting patent statutes in ways that make patent eligibility 'depend simply on the draftsman's art.'" As purveyors of "the draftman's art," then it behooves us to ask whether claims perceived to be directed to "laws of nature" can, in fact, be written to pass Constitutional muster (since, regardless of the Court's disdain, "the name of the game is [still] the claim").

A good place to start is with the Prometheus claims themselves. Although the Court focused on claim 1 of U.S. Patent No. 6,355,623:

1. A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:
(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and
(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,
wherein the level of 6-thioguanine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and
wherein the level of 6-thioguanine greater than about 400 pmol per 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

Claim 46 of of the '623 patent poses additional questions that must be addressed:

46. A method of optimizing therapeutic efficacy and reducing toxicity associated with treatment of an immune-mediated gastrointestinal disorder, comprising:
(a) determining the level of 6-thioguanine or 6-methylmercaptopurine in a subject administered a drug selected from the group consisting of 6-mercaptopurine, azathiop[u]rine, 6-thioguanine, and 6-methyl-mercaptoriboside, said subject having said immune-mediated gastrointestinal disorder,
wherein the level of 6-thioguanine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the[] amount of said drug subsequently administered to said subject, and
wherein the level of 6-thioguanine greater than about 400 pmol per 8x108 red blood cells or a level of 6-methylmercaptopurine greater than about 7000 pmol per 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

In the Supreme Court's decision the first step of claim 1 was discounted as merely selecting the population to be administered the drug and so could not impart any patent eligibility to the claim; the absence of this step in claim 46 would thus appear to do little to diminish its chances of being deemed patent-eligible. The Court also considered the determining step to be "conventional and routine." Recasting the claim as a method of treatment claim might improve its chances. For example:

1. A method of administering 6-thiopurine to a patient in need thereof for treating an immune-mediated gastrointestinal disorder, comprising the step of administering a therapeutically effective amount of the drug that produces no less than 230 pmol and no more than 400 pmol per 8x108 red blood cells in blood from the patient.

This claim is not infringed by a doctor "thinking about" how to administer the drug, and its "conventionality" would need to be measured with regard to whether administering the drug to achieve these plasma levels was known in the prior art. In this conformation, the "law of nature" informs the physician how much of the drug should be administered; while implicit in the claim is the need to determine whether the administered amount produced between 230 pmol and 400 pmol per 8x108 red blood cells in blood from the patient, determining drug concentrations in blood from a patient is not recited as an affirmative limitation in the claim. Of course, the literal infringer thus becomes the physician in this claim, and the "deep pocket" liability will lie against the hospital or drug company that specifies the required determination. This is analogous to "companion diagnostic" testing recommended for certain drugs, for example, that determine sequence variants in drug detoxifying enzymes such as P450; here ultimate infringement liability would lie against a (generic) drug company that requires such testing under a regulatory scheme (like the Hatch-Waxman Act).

This stratagem apparently was employed by the drafters of the claims in Classen v. Biogen, where the Federal Circuit distinguished between claims that specified immunizing an individual according to a schedule for minimizing chronic immune-mediated disorder (claim 1 of U.S. Patent No. 6,638,739):

1. A method of immunizing a mammalian subject which comprises:
(i) screening a plurality of immunization schedules, by
(a) identifying a first group of mammals and at least a second group of mammals, said mammals being of the same species, the first group of mammals having been immunized with one or more doses of one or more infectious disease-causing organism-associated immunogens according to a first screened immunization schedule, and the second group of mammals having been immunized with one or more doses of one or more infectious disease-causing organism-associated immunogens according to a second screened immunization schedule, each group of mammals having been immunized according to a different immunization schedule, and
(b) comparing the effectiveness of said first and second screened immunization schedules in protecting against or inducing a chronic immune-mediated disorder in said first and second groups, as a result of which one of said screened immunization schedules may be identified as a lower risk screened immunization schedule and the other of said screened schedules as a higher risk screened immunization schedule with regard to the risk of developing said chronic immune mediated disorder(s),
(ii) immunizing said subject according to a subject immunization schedule, according to which at least one of said infectious disease-causing organism-associated immunogens of said lower risk schedule is administered in accordance with said lower risk screened immunization schedule, which administration is associated with a lower risk of development of said chronic immune-mediated disorder(s) than when said immunogen was administered according to said higher risk screened immunization schedule.

A method of determining whether an immunization schedule affects the incidence or severity of a chronic immune-mediated disorder in a treatment group of mammals, relative to a control group of mammals, which comprises immunizing mammals in the treatment group of mammals with one or more doses of one or more immunogens, according to said immunization schedule, and comparing the incidence, prevalence, frequency or severity of said chronic immune-mediated disorder or the level of a marker of such a disorder, in the treatment group, with that in the control group.

Of course, the '793 patent claim might be cast even more directly as an immunization method claim:

A method of immunizing a mammalian subject comprising the step of administering to a patient an immunogen that is immunologically specific for an infectious disease-causing organism according to an immunization schedule that has a reduced risk for developing a chronic immune-mediated disorder(s).

While many of the claim terms ("immunization schedule," "reduced risk") will need to be defined expressly in the specification, the benefit of this claim structure is that it is specific (and can be made even more specific, e.g., the pathogen that the patient is immunized against) and does not require that the particular immunization schedule is determined as part of the claim. A criticism of these claims could arise if the immunogenic antigen was known and administered in a conventional fashion; however, it is possible also that the manner, formulation, frequency, or other aspect of how the immunogen is administered is not "routine" or "conventional."

The Myriad claims invalidated by the District Court (affirmed by the Federal Circuit and not included in the certiorari writ) fail for reasons satisfactorily embodied in Bilski:

1. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1.

1. A method for screening a tumor sample from a human subject for a somatic alteration in a BRCA1 gene in said tumor which comprises gene comparing a first sequence selected form the group consisting of a BRCA1 gene from said tumor sample, BRCA1 RNA from said tumor sample and BRCA1 cDNA made from mRNA from said tumor sample with a second sequence selected from the group consisting of BRCA1 gene from a nontumor sample of said subject, BRCA1 RNA from said nontumor sample and BRCA1 cDNA made from mRNA from said nontumor sample, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA from said tumor sample from the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA from said nontumor sample indicates a somatic alteration in the BRCA1 gene in said tumor sample.

1. A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject.

1. A method for identifying a mutant BRCA2 nucleotide sequence in a suspected mutant BRCA2 allele which comprises comparing the nucleotide sequence of the suspected mutant BRCA2 allele with the wild-type BRCA2 nucleotide sequence, wherein a difference between the suspected mutant and the wild-type sequences identifies a mutant BRCA2 nucleotide sequence.

2. A method for diagnosing a predisposition for breast cancer in a human subject which comprises comparing the germline sequence of the BRCA2 gene or the sequence of its mRNA in a tissue sample from said subject with the germline sequence of the wild-type BRCA2 gene or the sequence of its mRNA, wherein an alteration in the germline sequence of the BRCA2 gene or the sequence of its mRNA of the subject indicates a predisposition to said cancer.

The ACLU did not challenge all of Myriad's method claims, however, and Myriad's counsel argued before the Federal Circuit that one of the deficiencies in plaintiffs' pleadings was that any alleged injury was not redressable in view of Myriad's unchallenged claims, including (perhaps):

2. A method for diagnosing a predisposition for breast cancer in a human subject which comprises comparing the germline sequence of the BRCA2 gene or the sequence of its mRNA in a tissue sample from said subject with the germline sequence of the wild-type BRCA2 gene or the sequence of its mRNA, wherein an alteration in the germline sequence of the BRCA2 gene or the sequence of its mRNA of the subject indicates a predisposition to said cancer, wherein the detection in the alteration in the germline sequence is determined by an assay selected from the group consisting of
(a) observing shifts in electrophoretic mobility of single-stranded DNA on non-denaturing polyacrylamide gels,
(b) hybridizing a BRCA2 gene probe to genomic DNA isolated from said tissue sample,
(c) hybridizing an allele-specific probe to genomic DNA of the tissue sample,
(d) amplifying all or part of the BRCA2 gene from said tissue sample to produce an amplified sequence and sequencing the amplified sequence,
(e) amplifying all or part of the BRCA2 gene from said tissue sample using primers for a specific BRCA2 mutant allele,
(f) molecularly cloning all or part of the BRCA2 gene from said tissue sample to produce a cloned sequence and sequencing the cloned sequence,
(g) identifying a mismatch between (1) a BRCA2 gene or a BRCA2 mRNA isolated from said tissue sample, and (2) a nucleic acid probe complementary to the human wild-type BRCA2 gene sequence, when molecules (1) and (2) are hybridized to each other to form a duplex,
(h) amplification of BRCA2 gene sequences in said tissue sample and hybridization of the amplified sequences to nucleic acid probes which comprise wild-type BRCA2 gene sequences,
(i) amplification of BRCA2 gene sequences in said tissue sample and hybridization of the amplified sequences to nucleic acid probes which comprise mutant BRCA2 gene sequences,
(j) screening for a deletion mutation in said tissue sample,
(k) screening for a point mutation in said tissue sample,
(l) screening for an insertion mutation in said tissue sample,
(m) in situ hybridization of the BRCA2 gene of said tissue sample with nucleic acid probes which comprise the BRCA2 gene.

26. A method for screening a tumor sample from a human subject for the presence of a somatic alteration in a BRCA1 gene in said tumor which comprises comparing BRCA1 polypeptide from said tumor sample from said subject to BRCA1 polypeptide from a nontumor sample from said subject to analyze for a difference between the polypeptides, wherein said comparing is performed by
(i) detecting either a full length polypeptide or a truncated polypeptide in each sample or
(ii) contacting an antibody which specifically binds to either an epitope of an altered BRCA1 polypeptide or an epitope of a wild-type BRCA1 polypeptide to the BRCA1 polypeptide from each sample and detecting antibody binding, wherein a difference between the BRCA1 polypeptide from said tumor sample from the BRCA1 polypeptide from said nontumor sample indicates the presence of a somatic alteration in the BRCA1 gene in said tumor sample.

These claims, while relying on the "natural law" that certain mutations are associated with breast cancer, do not recite assays that are "routine" or "conventional" according to the Prometheus analysis, inter alia, because they were unknown in the prior art.

So what are the take-home lessons from this inquiry? First, it is apparent that claims reciting "active" steps will be much harder to pigeonhole into the "laws of nature" category than claims like the invalidated Myriad or Prometheus claims, because unlike in Prometheus it should be harder to categorize this as merely "selecting a population." Second, claims reciting novel "determining" steps (wherein what is administered is novel, or the relationship between what is detected and a particular disease is novel, or the method by which a biological molecule is administered or detected is novel), should overcome the "merely routine" basis used by the Court in invalidating the Prometheus claims. The Justices also did not "decide whether were the steps at issue here less conventional, these features of the claims would prove sufficient to invalidate them." Finally, placing the "law of nature" in context, wherein the claim steps recite a method performed only when a "law of nature" is satisfied, may also suffice.

These ideas are certainly not exhaustive, and absent circumstances permitting reissue of affected patents, it is plain that the "settled expectations" of the patenting community be damned in view of the Prometheus decision. But that doesn't mean America's patent draftsmen are helpless. It just means we will need to keep the Supreme Court's proclivities on subject matter eligibility in mind when drafting claims going forward. After 30 years of a relatively benign patent law regime under the Federal Circuit, the skies have darkened and the seas are rough. But this too shall pass so long as we keep our eyes on our pole star: "the name of the game is the claim."

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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